EPIC Trial Shows Ponatinib Effective in CML

On Monday, the third day of the 56th Annual Meeting of the American Society of Hematology, held December 6-9, in San Francisco, Jeffrey H. Lipton, MD, PhD, chief of Hematology/Oncology and Stem Cell Transplantation at the Steven and Alexandra Cohen Children’s Medical Center of New York, presented results from the evaluation of ponatinib vs imatinib in CML (EPIC) trial. His talk, “EPIC: a phase 3 trial of ponatinib compared with imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase" (CP-CML).

Ponatinib is a potent oral tyrosine kinase inhibitor active against native and mutated forms of BCR-ABL, including T315I. It has been approved in the US and in Europe for the treatment of adult patients with refractory CML or Philadelphia chromosome-positive acute lymphoblastic leukemia. Results from the phase 2 PACE study demonstrated that ponatinib is highly active in heavily pretreated Ph+ leukemia patients. With the EPIC trial, the authors wanted to evaluate the safety and efficacy of ponatinib in newly diagnosed CP-CML patients.

EPIC was a multicenter, international, phase 3, randomized, 2-arm, open-label trial of ponatinib (45 mg once daily) compared with imatinib (400 mg once daily) in newly diagnosed CP-CML. The patients (n = 528) were stratified by Sokal risk score (low [<0.8] vs intermediate [0.8 to ≤1.2] vs high [>1.2]), to either drug arm. End points analyzed were BCR-ABL <10% at 3 months; major molecular response (MMR), molecular response (MR)4, and MR4.5 rates at predetermined landmarks, and complete cytogenetic response (CCyR) rates at various landmarks. Dr Lipton informed the audience that the observation of arterial thrombotic events in the ponatinib development program resulted in the termination of the EPIC trial on October 18, 2013. Consequently, none of the prospectively defined endpoints could be analyzed, except the ones listed above.

When the study was terminated, 307 patients were randomized to receive ponatinib (n = 155) or imatinib (n = 152). The median follow-up was 5 months for ponatinib and 5.3 months for imatinib. Groups were well-balanced with respect to sex, age, pretreatment, and Sokal score; however, the proportion of patients with 1 or more cardiovascular risk factors (hypertension, hypercholesterolaemia, diabetes, obesity, and smoking) was higher in the ponatinib arm (n = 97, 63%) compared to the imatinib arm (n = 79, 52%). Dr Lipton said that 14 ponatinib and 2 imatinib patients discontinued due to adverse events (AEs). In the imatinib arm, 1 patient discontinued due to disease progression, 1 was lost to follow-up, and 4 patients died. Median duration of drug exposure, was 114 days in the ponatinib arm and 141 days in the imatinib arm. Dose reductions, were needed for 55 patients on ponatinib and in 10 on imatinib.

According to Dr Lipton, molecular response rates for ponatinib were uniformly higher compared with imatinib for all response measures and at all time points. “The percentage of patients who achieved <10% BCR-ABL at 3 months was significantly higher in the ponatinib arm compared with the imatinib arm overall, and also when patients were stratified by high-risk, intermediate-risk, and low-risk Sokal score,” he said. A significantly greater number of patients achieved MMR, MR4, and MR4.5 at any time in all Sokal risk groups with ponatinib than with imatinib. CCyR rates were significantly greater with ponatinib treatment at 6 months and at any time, compared with imatinib.

With respect to AEs, Dr Lipton noted that ponatinib treatment caused expected AEs, and that there were very few grade 3 or 4 toxicities. The most common were rash (38%), abdominal pain (36%), headache (33%), constipation (27%), increased lipase (27%), myalgia (26%), and thrombocytopenia (25%); with imatinib, they were nausea (34%), muscle spasms (34%), and diarrhea (27%). Serious treatment-emergent AEs (SAEs) occurring in ≥3 ponatinib patients were pancreatitis (n = 5), atrial fibrillation (n = 3), and thrombocytopenia (n = 3); no individual SAEs occurred in ≥3 imatinib patients. Eleven (7%) ponatinib and 3 (2%) imatinib patients experienced arterial thrombotic events, designated serious for 10 [7%] ponatinib and 1 [0.7%] imatinib patient(s). One patient in the ponatinib arm experienced a serious venous thromboembolic event: there were none in the imatinib arm. Ten of 11 ponatinib patients, and 2 of 3 imatinib patients with arterial thrombotic events had 1 or more cardiovascular risk factors.

“Despite early termination, at a median follow-up of 5.1 months, preliminary analysis suggests that ponatinib has improved efficacy over imatinib in newly diagnosed CP-CML patients, but has a higher AE rate, including [arterial thrombotic events] at the dose studied. Ponatinib emerged as a much superior TKI than imatinib, with deeper, more rapid response rates,” said Dr Lipton. He noted that a future dose-ranging trial of ponatinib in refractory CML has been planned to evaluate the benefit to risk ratio of alternate dosing regimens.